1,4-Dimethoxy naphthalenecarboxamide anticonvulsants

ABSTRACT

Compounds of the formula ##STR1## where R is a methyl, ethyl or propyl group and n is 1 or 2 and their nontoxic salts are useful as anticonvulsants.

FIELD OF INVENTION

This invention relates to novel compounds, the synthesis of saidcompounds and their use in treating grand mal epilepsy. Moreparticularly, this invention relates to novel naphthalene carboxamidesand their nontoxic salts, their synthesis from 1,4-dimethoxynaphthaleneand their use in treating convulsions and seizures resulting fromepilepsy.

BACKGROUND OF THE INVENTION

Epilepsy is a disease, which has been known for a long period of time,causing seizures and convulsions. There are various drugs on the marketfor the treatment of epilepsy; however, unfortunately, many of thepresent drugs cause serious side effects or are toxic. One drug now usedin the treatment of epilepsy is phenytoin (Dilantin). Dilantin iseffective in preventing seizures and convulsions caused by epilepsy;however, it has serious chronic side effects such as megaloblasticanemia and osteomalacia. Another well known drug for the treatment ofepilepsy is valproic acid. This compound, unfortunately, must be givenin large dosages to be effective; in fact, dosages very close to thosewhich are acutely toxic.

SUMMARY OF THE INVENTION

It has now been found that certain 1,4-dimethoxynaphthalenecarboxamidesand their nontoxic salts are highly effective in the treatment ofseizures and convulsions caused by epilepsy, while at the same timeexhibiting low acute toxicity and possessing few side effects. Thetherapeutic compounds of this invention are1,4-dimethoxynaphthalenecarboxamides having the general formula ##STR2##wherein R is selected from methyl, ethyl and propyl groups and n iseither 1 or 2 and their nontoxic salts.

DETAILED DESCRIPTION OF THE INVENTION

As indicated above, the novel therapeutic compounds of this inventionare 1,4-dimethoxynaphthalenecarboxamides and their nontoxic salts havingthe general formula shown above. Typical nontoxic salts are the acidsalts, as for example, the tartrate, bitartrate, acetate, citrate,maleate, malate, methane-sulfonate, sulfate, phosphate, hydrochloride,hydrobromide and the like. These compounds can be easily synthesizedstarting from the known compound 1,4-dimethoxynaphthalene. Thedimethoxynaphthalene can be prepared by the method of L. Fieser, Journalof the American Chemical Society, Volume 70, pages 3165 (1948).

The process of preparing the novel compounds of this invention comprisesthe steps of (1) brominating 1,4-dimethoxynaphthalene with liquidbromine in an organic solvent such as acetic acid at room temperature toform the 2-bromo-1,4-dimethoxynaphthalene, (2) converting the brominederivative to the carboxylic acid derivative by lithiation andcarboxylation. The lithiation is conducted in a known procedure, as forexample, by treating the bromo derivative with n-Butyllithium in anorganic solvent under anhydrous conditions at a low temperature, such as-78° C. The resulting lithium compound is not isolated, but convertedinto the carboxylic acid by adding dry ice to the cooled lithiumcompound and allowing the reaction mixture to come to room temperature.(3) The carboxylic acid derivative is then converted to the acidchloride by treating with thionyl chloride at room temperature. (4) Theresulting acid chloride is condensed with the appropriate amine to formthe carboxamide. The condensation reaction is carried out by treatingthe acid chloride in an organic solvent with the appropriate amine atroom temperature in the presence of a proton acceptor.

The compounds of this invention are particularly effective insuppressing grand mal convulsions and psychomotor seizures caused byepileptic disorders. In order to suppress seizures or convulsions, thecompounds of this invention can be administered by any acceptablepharmaceutical route, such as intramuscularly, subcutaneously,intravenously or orally. Most preferably, the compounds will beadministered orally by tablet or capsule containing about 25 to about200 mg of the compound. Normal dosages for humans will be from about 1to about 50 mg per kilogram, most probably about 10 to about 30 mg perkilogram of body weight, administered in multiple daily dosages. Toavoid the multiple daily dosages, it may be desirable in certain casesto microencapsulate the compounds or to compound them in the form ofspansules, which take effect over a longer period of time. Themicroencapsulation of these compounds is carried out in accordance withnormal procedures known to those skilled in the art such as shown inU.S. Pat. Nos. 4,316,884 and 3,155,590 the disclosures of which areincorporated herein by reference. Slow release oral administration maybe the most desired method of administration, although the other methodsdisclosed above are quite acceptable.

The compounds of this invention are solids having a low toxicity andhigh safety ratio. Compounds of this invention have an approximatelyLD₅₀ of around 750. In other words, it requires approximately 750 mg perkilogram of body weight to kill 50% of the animals administered thedrug. The compounds, in addition, have a low ED₅₀. In other words, onlya small amount of the compound is required to suppress convulsions orseizures in 50% of the animals treated. The approximate safety ratio ofthe compound is determined by dividing the LD₅₀ by the ED₅₀, which inthe case of the instant compounds, is relatively high. Thus, largeramounts of the instant compounds can be administered to patients in needof such treatment without concern that the compounds will be toxic.

In preparing medicaments using the compounds of this invention, it ispossible to mix the compounds with the normal additives, excipients,etc. used in preparing a pharmaceutical composition, such aspregelatinized starch, lactose, or the like.

The following examples will serve to illustrate the instant invention.Parts and percentages are by weight unless indicated otherwise.

EXAMPLE 1

This example illustrates the preparation of a typical1,4-dimethoxynaphthalenecarboxamide.

To a solution of 50 grams (0.26 mol) of 1,4-dimethoxynaphthalene,prepared according to the procedure of L. Fieser, in the Journal of theAmerican Chemical Society, Volume 70, page 3165 (1948), in 500 mlglacial acetic acid is added 13.7 ml (0.26 mol) of bromine at roomtemperature. The mixture is stirred for 1 hour, and the solvent isremoved under reduced pressure and the residue dissolved in ether. Theresulting solution is carefully washed twice with sodium bicarbonate,the organic layer separated, dried over sodium sulfate and the solventremoved. Distillation of the residue gave 63.4 grams (81% of theoreticalyield) of liquid 2-bromo-1,4-dimethoxy-naphthalene (boiling 200°-210° at0.1 mm Hg). The product has a nuclear magnetic resonance spectrumconsistant with the expected structure and has peaks expressed in partsper million relative to tetramethylsilane at 8.0 (m,2H), 7.4(m,2H),6.9(s,1H), 3.9(d,6H).

A solution of 15.0 grams (0.056 mol) of the above2-bromo-1,4-dimethoxynaphthalene in 300 ml of tetrahydrofuran, preparedunder anhydrous conditions, is cooled to -78° C. To this is added 35.1ml of a 1.6M solution of n-butyllithium in hexane. The resulting mixtureis stirred 10 minutes and copious amounts (about 30 grams) of powdereddry ice which has been washed in anhydrous ether are added. The reactionmixture is allowed to warm to room temperature; after 3 hours water isadded and most of the solvent removed under reduced pressure. Theresidue is partitioned between ether and 2M sodium hydroxide, theaqueous layer separated, saturated with ammonium chloride, and the pHadjusted to 2 by the addition of 10% aqueous hydrochloric acid. Theresulting mixture is extracted three times with ether, the combinedorganic layers dried over sodium sulfate, and the solvent removed. Theresidue is crystallized from aqueous methanol to give 11.2 grams, (86%)of 1,4-dimethoxy-2-naphthanoic acid. The white crystalline product meltsat 169°-170° C. The nuclear magnetic resonance spectrum is consistentwith the expected structure and has peaks at 8.1(m,2H), 7.6(m,2H),7.15(s,1H), 4.0(d,6H). The product exhibited an infrared spectrum withmajor absortions in 2900 cm-¹ and 1690 cm-¹.

The 1,4-dimethoxy-2-naphthanoic acid, 14.3 grams (0.06 mol) is dissolvedin 50 ml of thionyl chloride and the resulting mixture stirred overnightat room temperature. The excess thionyl chloride is removed underreduced pressure and residue is recrystallized from hexane to give 14.2grams (94% of theoretical yield) of a green moisture-sensitivecrystalline product, melting point 89°-95° C. The nuclear magneticresonance spectrum is consistent with the expected structure and haspeaks at 8.2(m,2H), 7.8(m,2H), 7.2(s,1H), 4.0(d,6H).

To 0.004 mole of n,n-dimethylethylenediamine and 0.004 mole oftriethylamine, in 50 ml of anhydrous tetrahydrofuran is added 1.0 gram(0.004 mol), of 1,4-dimethoxy-2-naphthoyl chloride in one portion. Awhite precipitate is formed and the mixture stirred for three hours. Asmall amount of water is added, and the solvent removed under reducedpressure. The residue is partitioned between 10% aqueous sodiumhydroxide and ether. The organic layer is separated, washed with brine,dried over potassium bicarbonate and solvent removed. The residue isdissolved in anhydrous ether and a slow stream of hydrogen chloride gasbubbled through the mixture for 10 minutes. The product is collected andrecrystallized from chloroform-hexane as a white crystal product havinga melting point of 93°-95° C. The product is sparingly soluble in waterand in ethyl alcohol. An elemental analysis for1,4-dimethoxy-N-(2-dimethylaminoethyl) -2-naphthalene carboxamidehydrochloride: calculated C:60.26%, H:6.79%, N:8.27%, found: C:59.90%,H:7.12%, N:7.91%. The NMR spectrum is determined and found to beconsistent with the expected structure having peaks at 8.05 (m,2H),7.4(m,3H), 3.95(s,3H), 3.8(s,3H), 3.6(q,2H), 2.5(t,2H), 2.2(s,6H).

EXAMPLE 2

This example illustrates the preparation of another typical1,4-dimethoxynaphthalene carboxamide of this invention.

1,4-Dimethoxy-2-naphthanoyl chloride is prepared exactly as described inExample 1. To 0.004 mol of 1,1-dimethyl-1,3-propylenediamine and 0.004mol, of triethylamine in 50 ml of anhydrous tetrahydrofuran is added 1.0gram, 0.004 mol of 1,4-dimethoxy-2-naphthanoyl chloride in one portion.A white precipitate is formed and the mixture stirred for three hours. Asmall amount of water is added and the solvent removed under reducedpressure. The residue is partitioned between 10% aqueous sodiumhydroxide and ether. The organic layer is separated, washed with brine,dried over potassium carbonate and the solvent removed. The residue isdissolved in anhydrous ether and a slow stream of hydrogen chloride gasis bubbled through the mixture for 10 minutes. The product is collectedby filtration and recrystallized from chlorformhexane to give a whitecrystalline compound having a melting point of 89°-90° C. The product issparingly soluble in water and ethyl alcohol. Elemental analysis isconducted for the compound1,4-dimethoxy-N-(3-dimethylaminopropyl)-2-naphthlenecarboxamidehydrochloride, the calculated values are C:60.50%, H:6.86%, N:7.80%,found: C:60.56%, H:7.25%, N:7.80%. The NMR spectrum is consistent withthe expected structure having peaks at 8.1(m,2H), 7.4(m,3H), 4.05(s,3H),3.95(s,3H), 3.80 (q,2H), 2.4(multipilicity and integration obscured byneighboring peak), 2.3(s, integration obscured by neighboring peak),1.95(t,2H).

EXAMPLES 3 & 4

These examples illustrate the use of the compounds described in Examples1 and 2 in suppressing convulsions induced in mice by supramaxal shock.

Male albino ICR-swiss mice fasted for 5-6 hours and weighing 20-26 gramsare used in all procedures. The compounds of the Examples 1 and 2 aredissolved in water and administered in dosages of 0.01 cc per gram bodyweight to groups of twelve mice via oral gavage at the milligrams perkilograms per body weight in the table below. One hour afteradministration of the compound, the mice are given a transcranalelectroshock, 60 hertz, 25 milliamps of 0.2 second duration. Thisstimulus is approximately 3 times the current required to produce tonicflexion-extension convulsions in 100% of the control mice tested. Theanimals are then observed, and the number undergoing convulsion noted.When the ED₅₀ is bracketed (at least one dose above and one dose below),an estimate of the ED₅₀ is calculated. The acute LD₅₀ is determined asfollows: Groups of four mice each are given selected doses of the testcompound and placed in plastic cages with food and water ad lib.Twenty-four hours later, the number of dead mice is noted. When the LD₅₀is bracketed (at least one dose above and one below) an estimate of theLD₅₀ is calculated. The results of the tests are averaged and tabulatedin Table 1. The values for Valproic acid and Dilantin are included inthe table for comparison.

    __________________________________________________________________________                 Supramaximal Electroshock                                                                   Acute (24 hr.)                                                  Antagonism    Toxicity  Approximate                                           Approximate ED.sub.50                                                                       Approximate LD.sub.50                                                                   Safety Ratio                             Compound     Mg/Kg         Mg/Kg     LD.sub.50 /ED.sub.50                     __________________________________________________________________________    1,4-Dimethoxy-N--                                                                          45            750       17                                       (2-dimethylaminoethyl)-                                                       2-naphthalenecarboxamide                                                      hydrochloride                                                                 1,4-Dimethoxy-N--                                                                          75            750       10                                       (3-dimethylaminopropyl)-                                                      2-naphthalenecarboxamide                                                      hydrochloride                                                                 Valproic Acid                                                                              600           1,425     2.4                                      Dilantin     13            417       32                                       __________________________________________________________________________

What we claim and desire to protect by Letters Patent is: 1.1,4-Dimethoxy naphthalenecarboxamide having the general formula ##STR3##wherein R is selected from the group consisting of methyl, ethyl andpropyl groups and n is a whole number from 1 to 2 and its nontoxicsalts.
 2. The compound of claim 1 wherein n is
 1. 3. The compound ofclaim 1 wherein n is
 2. 4. The compound of claim 1 wherein R is methyl.5. The compound of claim 1 wherein R is ethyl.